Progesterone for the treatment or prevention of spontaneous preterm birth

ABSTRACT

A method for treating or preventing spontaneous preterm birth in pregnant women and improving neonatal morbidity and mortality. The method includes administering to a pregnant woman in need thereof an effective amount of progesterone sufficient to prolong gestation by minimizing the shortening or effacing of her cervix. Treatment and prophylaxis with progesterone in pregnant women having symptoms of short cervix has been clinically shown to increase neonatal health.

CROSS-REFERENCE TO PRIOR APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 12/024,756, which was filed on Feb. 1, 2008, entitled“PROGESTERONE FOR THE TREATMENT OR PREVENTION OF SPONTANEOUS PRETERMBIRTH,” which is hereby incorporated by reference in its entirety; thisapplication also claims the benefit of U.S. Provisional Application No.60/888,480, which was filed on Feb. 6, 2007, and U.S. ProvisionalApplication No. 60/973,667, which was filed on Sep. 19, 2007, thedisclosures of which are fully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a method for treating or preventingspontaneous preterm birth in pregnant women while improving neonatalhealth. More particularly, the invention relates to a method of treatingor preventing the onset of preterm labor leading to preterm birth byadministering to a pregnant woman an amount of progesterone that issufficient to prolong gestation by delaying the shortening or effacingof her cervix. Additionally, the invention relates to a method oftreating or preventing the onset of preterm labor while decreasingneonatal mortality and/or morbidity by administering to a pregnant womansymptomatic of a short cervix an effective amount of progesterone todelay labor and to decrease neonatal mortality and/or morbidity.

BACKGROUND OF THE INVENTION

It is generally known that pregnant women who experience spontaneouspreterm birth (PTB) begin with preterm labor (also interchangeablyreferred to herein as “premature labor”) and start having regularcontractions that cause their cervix to start to open or thin out(called dilation and effacement) and soften before they reach about 37weeks of gestation. If a woman delivers a baby before 37 weeks, it istypically and conventionally called a preterm birth and the baby isconsidered premature.

Preterm birth remains one of the most serious problems in obstetrics,with enormous impact on infants, their families, and our society.According to a recent study published by the Institute of Medicine, theincidence of preterm birth has grown 33% since 1981, and each yearapproximately 500,000 women deliver prematurely in the U.S. aloneresulting in a $26 billion annual cost of premature birth to ournation's healthcare system. It has recently been reported that pretermbirths occur in 15% of pregnancies in the developed world and 12.7% ofall births in the United States in 2006 and 12.4% of all births in theUnited States in 2004. See, e.g., Use of progesterone to reduce pretermbirth, American College of Obstetricians and Gynecologists CommitteeOpinion No. 291, Vol. 102, No. 5, November 2003, pages 1115-1116;Hamilton, B. E., Annal Summary of Vital Statistics: 2005, Pediatrics,Vol. 119, No. 2, February 2007, pages 345-360.

It is believed that a preterm birth prior to 32 weeks of gestationrepresents an extremely high risk of morbidity and mortality.Additionally, a preterm birth between 32 and 36 weeks of gestation hasbeen found to be particularly alarming as having a great number of atrisk infants. Preterm delivery accounts for 60-70% of infant mortality,and is a leading cause of health care expenditures in both the perinatalperiod and throughout life for infant survivors. Recent advances inmodern obstetric and neonatal care have led to improved infant survival,however, 55% of newborns with an extremely low birth weight (<1000 g) ordelivered very premature (<28 weeks) who survive to middle childhoodshow evidence of clinically significant cognitive, educational, andbehavioral impairment.

Approximately 20%-30% of preterm births are the result of a physician'sdecision to bring about delivery for maternal or fetal indications. Theremainder of preterm deliveries is spontaneous, usually following theonset of premature labor or rupture of the membranes. Several riskfactors for preterm labor have been identified including: multi-fetalgestation, maternal stress, systemic and intrauterine infection, race,and socioeconomic status. The Preterm Prediction Study found that ahistory of prior spontaneous preterm delivery was a strong predictor ofsubsequent preterm delivery with a prior delivery at 23-27 weeks givingrise to an 11-fold increase in the risk. Unfortunately, however, riskassessment methods using only historical risk factors have anunacceptably low sensitivity and poor predictive value. Supplementinghistorical-based risk assessment with technology, specifically anultrasonographic assessment of the cervix, adds improved sensitivity andspecificity. Ultrasound identification of cervical shortening iscorrelated with a logarithmic increase in the risk of preterm delivery.See Jams et al, The length of the cervix and the risk of spontaneouspremature delivery, N. Engl. J. Med. 1996; 334: 567-572.

Of the surviving premature infants, many are afflicted with lifelongdifficulties such as cerebral palsy, mental retardation, chronic lungdisease, hearing and vision deficits, and learning disabilities. Themore mature a child is at birth, the more likely he or she is to surviveand the less likely he or she is to have related health problems.Premature babies born between 34 and 37 weeks are generally relativelyhealthy. If a woman goes into labor before 34 weeks, however, the risksof adverse health effects and/or medical complications increase.

It is generally known that the length of a woman's cervix is a goodindication of whether a pregnant woman will experience preterm labor andpreterm birth. Physicians routinely check the length of a woman's cervixat the first prenatal visit, so that they can monitor changes incervical length as the pregnancy progresses. If a woman's cervix getsshorter at midpregnancy, it means that the cervix is beginning to efface(thin out), and it is a good indication that the woman is at higher riskfor preterm delivery.

Cervical shortening, and to some degree such characteristics as previouspreterm birth history, age, ethnicity, body mass index (BMI) andcervical surgery, are conventionally known risk factors related topreterm birth. Data support an inverse relationship between cervicallength and preterm delivery. In a prospective study of 2915 women thatinvestigated the relationship between short cervical length and pretermdelivery, researchers found that even a small decrease in cervicallength between the 24^(th) and 28^(th) weeks of gestation was associatedwith an increased risk of preterm birth (RR 2.03; 95% CI, 1.28-3.22).See Iams et al, The length of the cervix and the risk of spontaneouspremature delivery, N. Engl. J. Med. 1996; 334: 567-572. At 24 weeks,when compared with women whose cervical length was above the 75^(th)percentile of normal, women who had a cervical length in the 25^(th)percentile (<3.0 cm) had a relative risk of preterm delivery of 3.79(95% CI, 2.32-6.19); those in the 10^(th) percentile (<2.6 cm) had arelative risk of 6.19 (95% CI, 3.84-9.97); those in the 5^(th)percentile (<2.2 cm) had a relative risk of 9.49 (95% CI, 5.95 to15.15); and those in the 1^(st) percentile (<1.3 cm) had a relative riskof 13.99 (95% cm 7.89 to 24.78). Id. Other studies have determined thatmonitoring cervical length may aid in the identification of women at anincreased risk for recurrent preterm birth. See Spong, C., Predictionand prevention of recurrent spontaneous preterm birth, American Collegeof Obstetricians and Gynecologists, Vol. 110, No. 2, Part 1, August2007, pages 407-408.

There is currently no approved therapy for preventing preterm births inthe United States. See Institute of Medicine Report on Preterm Birth,2006. Existing medical practice for preventive treatments regarding ashort cervix early in gestation involves mechanical/surgical treatments.For example, cervical cerclage is a surgical procedure where the cervixis sewn or stitched closed, thus physically preventing the cervix fromprematurely shortening or thinning out. The stitches are then removed,typically at about week 37, to allow normal dilation of the cervixduring labor. Unfortunately, typical adverse effects associated withcervical cerclage procedures include risk of premature contractions,cervical dystocia (inability of the cervix to dilate normally duringlabor), cervical infections, and other risks generally associated withsurgical procedures. In addition, there is controversy about theeffectiveness of cerclage in the treatment of a short cervix. Severalrecent studies suggest this surgical treatment is no better thanplacebo. Although cervical length, specifically cervical shortening isknown to be correlated to preterm birth, no non-surgical intervention ispresently known to be efficacious. See Spong, C., pages 407-408. Thatis, there is currently no accepted medical treatment for the risk factorfor preterm labor and birth known as “short cervix”.

Progesterone administration has been advocated for the prevention ofpreterm birth in certain women considered to be at high risk, althoughthe primary focus has been on patients with a prior history of pretermbirth. The efficacy of vaginally administered progesterone to preventpreterm birth in women at especially high risk of preterm delivery,particularly women experiencing cervical shortening, is far fromconcrete and is largely unknown. O'Brien et al., for example, havedetermined that prophylactic treatment with vaginal progesterone geldoes not effectively reduce the frequency of recurrent preterm birth inhigh risk women selected by a history of spontaneous preterm birth. Asprovided by the Committee on Obstetric Practice of the American Collegeof Obstetricians and Gynecologists in the publication, Use ofProgesterone to Reduce Preterm Birth, American College of Obstetriciansand Gynecologists Committee Opinion No. 291, Vol. 102, No. 5, November2003, pages 1115-1116, the ideal progesterone formulation is unknown,however.

The use of progesterone to treat all women at risk for preterm birthdoes not have unqualified support at present. Several authors haveexpressed the need for adequately designed, randomized trials in largerpopulations to identify the ideal progesterone formulation and dosage,and to demonstrate a decline in preterm births before 37 weeks and areduction in perinatal morbidity and mortality. See, e.g., Dodd et al,Prenatal administration of progesterone for preventing preterm birth,Cochrane Database Syst Rev 2006.

While there is much debate regarding the use of progesterone regardingbirth, specifically regarding the period of gestation, there is little,if any, conventional art analyzing effects to neonatal populations basedon treatments for preventing preterm birth. Meta-analysis of randomizedtrials involving women revealed that there may be a reduction in therisk of preterm birth less than 37 weeks and 34 weeks. Dodd, J. M. etal, Prenatal administration of progesterone for preventing preterm birth(Review), The Cochrane collaboration, John Wiley Sons, Ltd, 2006, pages1-36. Importantly, however, there was no statistically significantdifference in the occurrence of perinatal death between womenadministered progesterone and those administered placebo. Dodd, J. M. etal, pages 4-5. In fact, no differences were reported regarding neonataloutcomes between the placebo and progesterone groups. Dodd, J. M. et al,pages 4-5; Mackenzie, R. et al., Progesterone for the prevention ofpreterm birth among women at increased risk. A systematic review andmeta-analysis of randomized controlled trials, Journal of Obstetrics andGynecology, 194, 2006, pages 1234-42.

One study provided information regarding pregnancy prolongation and themorbidity of the child. Lam, F. et al., Evaluation of the pregnancyprolongation index (PPI) as a measure of success of obstetricinterventions in the prevention of preterm birth and associatedmorbidities, Journal of Obstetrics and Gynecology, 192, 2005, 2047-54.This study, however, provided no comparative experimental data betweentreatment groups and control groups. Moreover, this study did not relateto use of progesterone for treatment or prophylaxis of preterm birth.Ultimately, this study was limited to examining neonatal health simplyas a function of gestational age at delivery rather than as aconsequence of a treating/prophylactic agent.

Thus, there is a need for a method of treating or preventing the onsetof preterm labor and resulting preterm birth in pregnant women,particularly for women having a short cervix, without the adverse healtheffects that are typically associated with currently known methods.Moreover, beyond just focusing on the health of the mother giving birth,there needs to be a strong focus on, and intervention for, improvingneonatal outcome. That is, preterm birth is associated with highperinatal morbidity and mortality; and suppression of premature laborhas not conventionally been associated with improved infant outcomes.The conventional art does not show any direct health benefits to theneonate. Therefore, there is a need in the art for treatment and/orprophylaxis to improve natal, particularly neonatal, health for birthsoccurring preterm.

SUMMARY OF THE INVENTION

The present invention is directed to a method for treating or preventingthe onset of preterm labor and subsequent preterm birth in pregnantwomen. In a preferred embodiment, the method includes administering to apregnant woman in need thereof an effective amount of progesterone thatis sufficient to prolong gestation by delaying the shortening oreffacing of the cervix. Preferably, the progesterone is administered asa vaginal gel, as a vaginal suppository, as vaginal cream, or a vaginalsolid dosage form (such as a tablet), or through means of a deliverydevice inserted into the vagina, such as a cervical ring or otherdevices as generally known in the art.

The present invention provides a method of improving neonatal health,i.e., morbidity and/or mortality, in births by women with short cervicallength in mid-pregnancy. The method of improving neonatal morbidity andmortality comprising administering to a pregnant woman with a short oreffaced cervix in need thereof an effective amount of progesteronesufficient to prolong gestation. In some embodiments, neonates born towomen receiving progesterone treatment and/or prophylaxis arecharacterized by decreased neonatal morbidity and mortality, decreasednumber of neonatal intensive care unit (NICU) Days, decreased likelihoodof admission into the NICU, or a combination thereof, as compared tobabies born to mothers not provided an effective amount progesteroneduring gestation. In preferred embodiments, between about 45 mg and 800mg of progesterone, either natural or synthetic or a derivative thereof,is administered as a vaginal gel. In yet additional embodiments, theprogesterone is administered daily beginning about the 18^(th) to22^(nd) week of gestation until about the 37^(th) week of gestation, forpreferably about 14 to 19 weeks.

In still other embodiments of the present invention, the progesterone isadministered to a pregnant woman whose cervix has a length greater thanabout 1.0 cm and more preferably greater than 1.5 cm, wherein theprogesterone is administered to a pregnant woman whose cervix has alength between about 1.0 cm and 8.0 cm. In variations, the length of thecervix in women who are administered progesterone is less than or equalto about 3.0 cm, preferably less than 2.8 cm and even more preferablyless than 2.5 cm.

In the embodiments of the present invention, the progesteroneadministered can be progesterone molecule (from any source, includingnatural or synthetic) or progesterone metabolites (from any source,including natural or synthetic), or any other progestin. Progesteroneitself is preferred, although other progestins may be used. Wheresynthetic progestin is used, preferably, the synthetic progesterone isselected from a group consisting of derivatives of progesterone or oftestosterone or derivatives of other molecules with progestogenicactivity. Such progestins include, but are not limited to17-alpha-hydroxyprogesterone caproate, medroxyprogesterone acetate,norethindrone, norethindrone acetate, norethindrone enanthate,desogestrel, levonorgestrel, lynestrenol, ethynodiol diacetate,norgestrel, norgestimate, norethynodrel, gestodene, drospirenone,trimegestone, levodesogestrel, gestodyne, nesterone, etonogestrel, andderivatives from 19-nor-testosterone. In a preferred embodiment, theprogesterone includes either of the natural progestins, progesterone or17-alpha-hydroxyprogesterone. Some progestins can be deliveredvaginally, some by intramuscular injection, some by oral administration,and some by rectal administration, although other routes ofadministration can be used as known in the art. In a preferredembodiment, the progesterone is administered via a drug delivery systemthat comprises progesterone, a water-soluble, water-swellablecross-linked polycarboxylic acid polymer, and at least one adjuvant.

In a preferred embodiment, the progesterone is administered daily viathe vaginal route. However, the administration can be as infrequent asweekly or as often as 4 times daily, depending on the characteristics ofthe progestin and the progestin formulation. Preferably, theprogesterone is administered beginning about the 18^(th) to 22^(nd) weekof gestation until about the 37^(th) week of gestation, or forapproximately 14 to 19 weeks, depending on the gestational age at thebeginning of treatment and the date of delivery. In another embodiment,the progesterone is administered beginning about the 16^(th) week ofgestation until about the 37^(th) week of gestation, or forapproximately 21 weeks. In still other embodiments, the progesterone isadministered beginning about the time of a positive pregnancy test untilabout the 37^(th) week of gestation, or beginning about the 2^(nd) to4^(th) week of gestation, for approximately 33 to 35 weeks.

The amount of progesterone administered is preferably between about 45mg and 800 mg, and more preferably between about 90 mg and 250 mg, basedon the progestin effect of natural progesterone administered vaginally,but may be more or less depending on the potency of the progestin andthe route of administration. The progesterone is preferably administeredto a pregnant woman beginning as early as the onset of gestation andwhose cervix has a length greater than about 1.0 cm. More preferably,the progesterone is administered to a pregnant woman beginning as earlyas the onset of gestation and whose cervix has a length is at leastabout 1.0 cm and at most about 8.0 cm, and even more preferably, theprogesterone is administered to a pregnant woman whose cervix has alength less than or equal to 2.5 cm or 3.0 cm.

Another embodiment of the present invention is to provide improvedmethods of treating or preventing the onset of preterm labor andpremature birth by administering to a pregnant woman an amount ofprogesterone that is sufficient to minimize or delay the shortening oreffacing of her cervix, and possibly softening and dilating.

BRIEF DESCRIPTION OF THE DRAWINGS

Other features and advantages of the invention will become apparent fromthe description that will now be given, with reference to the appendedFigures, which show, by way of example but implying no limitation,possible embodiments of the invention.

FIG. 1 is a table that includes baseline data for participants in astudy that compared the efficacy of progesterone in the treatment ofpreterm births in placebo and treatment groups, in accordance with oneembodiment of the invention;

FIG. 2 is a table illustrating the trial profile of participants,according to one embodiment of the invention;

FIG. 3 is a table of data for participants with a short cervix of lessthan 2.8 cm, according to one embodiment of the invention;

FIG. 4 is a table that includes cervical length data at Week 28 forparticipants in the placebo and treatment groups, according to oneembodiment of the invention;

FIGS. 5 a and 5 b depict a delivery time curve for participants in theplacebo and progesterone treatment groups, according to an embodiment ofthe invention;

FIG. 6 is a delivery time curve for participants with a baselinecervical length of less than or equal to 3.2 cm, in accordance with oneembodiment of the invention;

FIG. 7 is a delivery time curve for participants with a baselinecervical length of greater than 3.2 cm, in accordance with oneembodiment of the invention;

FIG. 8 is a delivery time curve for participants having a baselinecervical length of less than or equal to 3.0 cm, according to oneembodiment of the invention;

FIG. 9 is a survival curve, evaluating pre-term delivery up to 37 weeksfor participants with a cervical length of less than or equal to 3.0 cm,according to one embodiment of the invention;

FIG. 10 is a delivery time curve for participants having a cervicallength of less than 2.8 cm, according to one embodiment of theinvention;

FIG. 11 is a table summarizing preterm birth outcomes in studyparticipants with a cervical length of less than 2.8 cm at enrollment,in accordance with one embodiment of the invention,

FIG. 12 is a table summarizing neonatal outcomes in participants with acervical length of less than 2.8 cm at baseline, according to oneembodiment of the invention;

FIGS. 13 a-e present graphs depicting infant outcomes in placebo andtreatment patients with a baseline cervical length ≦3.0 cm, inaccordance with one embodiment of the present invention; and

FIGS. 14 a-e present graphs depicting infant outcomes in placebo andtreatment patients with a baseline cervical length ≦2.8 cm, inaccordance with one embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It is generally unknown in the field of obstetrics to administerprogesterone to a pregnant woman with a short or effaced cervix for thepurpose of affecting cervical dilation and effacement in order to treator prevent the onset of preterm labor and premature birth. Inparticular, and to the best of our knowledge, there is no literature orother publications that teach or suggest that progesterone can beadministered to a pregnant woman with a short cervix to prolonggestation by minimizing the shortening or effacing of the cervix, andpossibly the softening and dilation.

The present invention is directed to improving neonatal health byadministering an effective amount of progesterone or derivative thereofto pregnant women having short or effaced cervixes. In preferredembodiments, the use of progesterone decreases the morbidity and/ormortality of neonates born to pregnant women symptomatic of a shortenedcervical length. In some variations, neonates, in whom the mother wastreated with progesterone, exhibit at least one of: 1) a decrease inneonatal intensive care unit (“NICU”) Days and 2) fewer percentageproportion of admission to the NICU, (i.e., a reduction in percentage ofbabies admitted in the NICU). The neonates born to women beingadministered progesterone during pregnancy also exhibit lower incidencesof neonatal disease and disorders, such as respiratory distress syndrome(RDS), intraventricular haemorrhage, necrotizing entercolitis, sepsis,and death, as compared to neonates in which the mother was notadministered progesterone during pregnancy. This evidence is indicativeof the decreased morbidity rate and shows that fewer babies are gettingsick by treatment and/or prophylaxis of the pregnant mother having shortcervix symptoms with progesterone. In accordance with this invention,treatment and prophylaxis of mothers exhibiting short cervix symptomsincreases the clinical health of the resulting neonate and decreases thefrequency of births on or before 37 weeks of gestation.

Embodiments of the present invention suggest that the use ofprogesterone in patients with short cervix produces a significantreduction in preterm birth (PTB) of less than or equal to 32 weeks ofgestation and/or a significant improvement in selected infant outcomes.Additionally, embodiments suggest that women have a short cervicallength, preferably less than 3.0 cm, and more preferably less than 2.8cm, benefited from progesterone therapy as a PTB intervention strategy.

As used herein, the term “preterm” generally describes human gestationresulting in birth prior to 37 weeks. Accordingly, “preterm” coversbirths occurring less than 35 weeks or less than or equal to 32 weeks ofgestation. Additionally, another definition of preterm labor includesdilation and/or effacement of the cervix, which is detected by digitalexamination, associated with persistent uterine contractions before 37weeks of gestation. In some embodiments as discussed herein, pretermlabor was defined as 6 or more uterine contractions per hour accompaniedby documented cervical change, cervical dilation greater than 2 cm,cervical effacement greater than 80%, or documented change in cervicaleffacement greater than 50%.

As used herein, short cervix describes a cervical length from greaterthan 1.0 to 3.5 cm, preferably from greater than 1.0 to 3.0 cm, morepreferably from greater than 1.0 to 2.5 cm, and even more preferablygreater than 1.0 to 2.0 cm. A cervix that is less than 1.0 cm iscommonly described as an “ultra-short cervix” and is clinicallydistinguishable from “short cervix.” How to identify and clinicallydiagnose pregnant women having short cervix would be understood by oneskilled in the art, and may include such methods as sonographicexamination and clinical examination, for example.

As used herein, neonatal encompasses children about 6 months of age orless, preferably about 3 months of age or less, more preferably about 2months of age or less, and even more preferably about 1 month of age orless. In certain embodiments, neonatal is used to encompass perinatal,preferably the period after birth.

As used herein, neonatal outcome (interchangeably referred to herein as“neonatal health”) is measured by mortality and morbidity incidences,prevalence, and clinical states. For example, health may be directlycorrelated to infant weight. Health may also be inversely related toincidence of special care admission (i.e., NICU) at birth, length ofneonatal hospital stay at birth, incidence of RSD, incidence ofintraventricular haemorrhage, incidence of necrotizing enterocolitis,incidence of sepsis, and incidence of neonatal death. Other measures ofmorbidity may be used by those skilled in the art.

The term “pharmaceutically effective amount” (or interchangeablyreferred to herein as “an effective amount”) has its usual meaning inthe art, i.e., an amount of a pharmaceutical that is capable of inducingan in vivo and/or clinical response that facilitates management,prophylaxis, or therapy. This term can encompass therapeutic orprophylactic effective amounts, or both. As used herein, the term“suitable” means fit for mammalian, preferably human, use and for thepharmaceutical purposes disclosed herein.

The term “treatment” or “treating” means any treatment of a disease ordisorder in a mammal, including: preventing or protecting against thedisease or disorder, that is, causing the clinical symptoms not todevelop; inhibiting the disease or disorder, that is, arresting orsuppressing the development of clinical symptoms; and/or relieving thedisease or disorder, that is, causing the regression of clinicalsymptoms. In some embodiments, the term “treatment” or “treating”includes ameliorating the symptoms of, curing or healing, and preventingthe development of a given disease.

The term “prophylaxis” is intended as an element of “treatment” toencompass both “preventing” and “suppressing,” as defined herein. Itwill be understood by those skilled in the art that in human medicine itis not always possible to distinguish between “preventing” and“suppressing” since the ultimate inductive event or events may beunknown, latent, or the patient is not ascertained until well after theoccurrence of the event or events.

Without being bound to any theory, it is believed that of all pretermbirths, women having short cervix account for about 20-30%. The presentinvention has surprisingly and unexpectedly discovered that thepopulation of women suffering from short cervix among women susceptible,predisposed, or associated with incidence of preterm birth, isresponsive to progesterone treatment, prophylaxis, and/or other therapyduring pregnancy to prevent, or reduce the incidence, of preterm births.Interestingly, there has been much debate in the art concerning the useof progesterone to reduce the incidence of preterm birth. FIGS. 5 a and5 b of this application suggests that there are no differences ingestation period between a treatment population of pregnant womenreceiving progesterone and a control population receiving placebo,wherein women in both groups have an average baseline cervical length ofgreater than 3.2 cm. FIGS. 6 & 7 show that the responding population ofshort cervix patients (see FIG. 6) are hidden in the total population ofresults (see FIGS. 5 a and 5 b) and that the longer cervix populationpatients (see FIG. 7) show no effect of progesterone similar to theoverall population (see FIGS. 5 a and 5 b). That is, the probability ofnot delivering early in the term is generally similar between the twogroups. In fact, statistically, the results are so buried, the prior artteaches away from expecting the results we achieved.

However, an examination of this short cervix population (e.g., cervicallength is less than or equal to 3.0 cm, as shown in FIG. 8, reveals thatwomen receiving progesterone have an increased probability fordelivering later during the pregnancy term than women receiving placebo.In FIG. 9, babies born to women who are administered progesterone have agreater chance of survival than babies born to women receiving placebodue to a reduction in preterm birth. See FIGS. 10, 11, and 12. Similarresults have been found in women having cervical lengths of less than2.8 cm.

The progesterone administered in accordance with the present inventioncan be progesterone molecule (from any source, including natural orsynthetic) or progesterone metabolites (from any source, includingnatural or synthetic), such as 17-alpha-hydroxyprogesterone, forexample, or it can be any other progestin. Any combination of these mayalso be used. In certain embodiments, the term “natural progesterone”includes progesterone and/or a natural progesterone metabolite.Progesterone itself is preferred, although other progestins may be used.Where synthetic progestin is used, preferably, the syntheticprogesterone is selected from a group consisting of derivatives ofprogesterone or of testosterone or derivatives of other molecules and/orcompounds with progestogenic activity. The term “derivative” refers to achemical compound that may be made from or lead to a parent compoundresulting from one or more chemical reactions. As used herein, the term“progestin” encompasses natural progesterone, synthetic progesterone,natural or synthetic derivatives of progesterone and/or otherprogestogenic compounds, or combinations thereof.

Thus progestins include, but are not limited to,17-alpha-hydroxyprogesterone caproate, medroxyprogesterone acetate,norethindrone, norethindrone acetate, norethindrone enanthate,desogestrel, levonorgestrel, lynestrenol, ethynodiol diacetate,norgestrel, norgestimate, norethynodrel, gestodene, drospirenone,trimegestone, levodesogestrel, gestodyne, nesterone, etonogestrel, andderivatives from 19-nor-testosterone. In a preferred embodiment, theprogesterone includes either of the natural progestins, progesterone or17-alpha-hydroxyprogesterone. Some progestins can be deliveredvaginally, some by intramuscular injection, some by oral administration,and some by rectal administration, although other routes ofadministration can be used as known in the art. In a preferredembodiment, the progesterone is administered via a drug delivery systemthat comprises progesterone, a water-soluble, water-swellablecross-linked polycarboxylic acid polymer, and at least one adjuvant.

In a preferred embodiment, the progesterone is administered daily, viathe vaginal route. However, the administration can be as infrequent asweekly or as often as 4 times daily, depending on the characteristics ofthe progestin and the progestin formulation, including concentration androutes of administration. Preferably, the progesterone is administeredbeginning about the 18^(th) to 22^(nd) week of gestation until about the37^(th) week of gestation, or for approximately 14 to 19 weeks,depending on the gestational age at the beginning of treatment and thedate of delivery. In another embodiment, the progesterone isadministered beginning about the 16^(th) week of gestation until aboutthe 37^(th) week of gestation, or for approximately 21 weeks. In stillother embodiments, the progesterone is administered beginning about thetime of a positive pregnancy test until about the 37^(th) week ofgestation, or beginning about the 2^(nd) to 4^(th) week of gestation,for approximately 33 to 35 weeks.

The progesterone is preferably administered to a pregnant womanbeginning as early as the onset of gestation and whose cervix has alength greater than about 1.0 cm, or more preferably greater than 1.5cm. More preferably, the progesterone is administered to a pregnantwoman beginning as early as the onset of gestation and whose cervix hasa length is at least about 1.0 cm and at most about 8.0 cm, and evenmore preferably, the progesterone is administered to a pregnant womanwhose cervix has a length less than or equal to 3.0 cm or less than orequal to 2.5 cm in more preferable embodiments.

The amount of progesterone administered is preferably between about 45mg and 800 mg, and more preferably between about 90 mg and 250 mg, basedon the progestin effect of natural progesterone administered vaginally,but may be more or less depending on the potency of the progestin, thedelivery system, and the route of administration. The concentration ofprogesterone is from about 0.01% to about 50%, preferably from about 1%to about 40%, more preferably from about 2.5% to about 30%, even morepreferably from about 5% to about 20%, and still more preferably fromabout 6% to about 15%. In the most preferred embodiments, theconcentration of progesterone is from about 7% to about 9%.

For some embodiments, the amount and concentration of the progesteroneneeds to be sufficient to remain in the subject to provide prophylaxisor treatment, such as for about 1 hour or more, preferably greater thanabout 2 hours, even more preferably greater than 6 hours, still morepreferably greater than about 12 hours, yet more preferably greater thanabout 24 hours, and most preferably greater than about 36 hours.

For some embodiments, the method of administration may includeadministered, parenterally, by injection, orally, topically,intravenously, intraperitoneally, subcutaneously, transcutaneously,intradermally, subdermally, intra-articularly, intraventricularly,intrathecally, intravaginally, or intramuscularly. Additionalformulations that are suitable for other modes of administration includesuppositories and, in some cases, through a buccal, sublingual,intraperitoneal, intravaginal, anal or intracranial route. In preferredembodiments, the method of administration is vaginal.

In certain embodiments, the progesterone is provided in solution, suchas an oil or otherwise suitable carrier as understood by one skilled inthe art. Other methods of delivery, such as oil-based capsules andsuppositories, are also available in certain embodiments. Forsuppositories, any traditional binder and/or carrier may be used, forexample, one or more polyalkalene glycols or triglycerides; suchsuppositories may be formed from mixtures containing the activeingredient in the range of preferably about 0.5% to 10%, more preferablyabout 1 to 2%. Oral formulations may include such normally employedexcipients as, for example, pharmaceutically acceptable mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, and the like, or any combination.

Embodiments of the present invention administer the progesterone as manytimes per day as needed to be effective to prevent and/or treat pretermbirth, i.e., delay birth and increase gestation, preferably more than orequal to 37 weeks. In certain variations of these embodiments, thedosing of progesterone is 1 to 4 times per day. It should understood toone skilled in the art that the frequency of administration per dayvaries by the concentration and amount of progesterone delivered. Forexample, 90 mg of 8% progesterone delivery systems are preferablyadministered once per day. In other embodiments, 200 mg progesterone isadministered 2 to 4 times per day.

Some embodiments of the present invention deliver the progesteronetogether with or in a composition having a pharmaceutically acceptablebioadhesive carrier that comprises a cross-linked carboxylic polymer.Certain variations of these embodiments include a water-swellablepolycarboxylic acid polymer, that upon administration provide localdirected tissue levels and efficacy without detrimental blood levels ofthe treating agent.

In preferred embodiments of the present invention, compositions of thepresent invention are useful for vaginal administration. For example,the vaginal route of administration may be chosen due to its potentialfor greater patient satisfaction compared with intramuscular dosing, andfor improved efficacy through enhanced drug delivery to target tissues.The bioadhesive formulations of the invention have been found to providelocal vaginal administration of progesterone useful local drug levelswhile avoiding levels that give rise to undesirable side effects.Vaginal administration also avoids first-pass metabolism problems, e.g.,provides a first uterine pass effect, and direct delivery to the uterusallows for lower systemic drug concentrations.

In preferred embodiments, the progesterone is administered in abioadhesive formulation of progesterone for vaginal applicationconsisting of a polycarbophil-based gel that contains 8% (wt/wt)progesterone. In the most preferred embodiments, the progesterone isdelivered as 8% progesterone gel and placebo, commonly available asProchieve® or Replens®, which are manufactured by Columbia Laboratories,Inc., NJ. In some embodiments, the progesterone is delivered in aprefilled, single-use, disposable plastic applicator that delivers thedose of 1.125 g of gel containing 90 mg of progesterone. Embodiments ofthe present invention deliver progesterone in accordance with U.S. Pat.No. 5,543,150 from U.S. patent application Ser. No. 08/122,371, which isincorporated herein in its entirety.

The methods disclosed of the present invention may be used inconjunction with other methods of preventing and/or treating pretermbirth and/or short cervix in pregnant women, such as surgical cerclage,administration of complementary/supplementary compositions such asantibiotics, indomethacin, and polymeric compositions, for example.Accordingly, the present invention is suitable for combination therapy.

EXAMPLES

The present invention is further illustrated by the following examplesthat are merely for the purpose of illustration and are not to beregarded as limiting the scope of the invention or the manner in whichit can be practiced. While the results of the study show thatprogesterone can be effectively administered to pregnant women havingbaseline cervix lengths between about 1.0 cm and 8.0 cm to treat orprevent the decrease in cervical length during gestation, and thus treator prevent the onset of preterm labor and premature birth, the followingexamples show increased efficacy in particular subgroups.

Example 1a A Randomized, Double Blind, Placebo Controlled Test of theEffects of Progesterone on Preterm Birth

In light of the state of the art, a study was conducted to examine theeffects of progesterone on preterm labor and premature birth in womenwith a history of a previous preterm birth. The baseline data for thestudy is provided in FIG. 1. The participants in the study included 611evaluable pregnant women, of which 308 were selected into a treatmentgroup and 302 were selected into a placebo group. The selection,categorization, and breakdown of the two groups is outlined in the flowchart of FIG. 2. The study was a prospective, randomized,placebo-controlled, double-blind, multicenter trial in pregnant subjectsat high risk of spontaneous preterm delivery. The study participantswere screened from 16 0/7 and 22 6/7 weeks gestational age. Subjectswere randomized to drug or placebo from 18 0/7 to 22 6/7 weeks.

Subjects meeting the study criteria were enrolled by the investigatorbetween 18 0/7 and 22 6/7 weeks and received identically packaged,sequentially numbered progesterone or placebo vaginal gel in a 1:1ratio. A SAS (SAS Institute Inc., Cary, N.C., USA) procedure forvariable block size was used to generate a randomization schedulestratified by study site and by inclusion criteria (prior preterm birthor short cervix). Quintiles, Inc. (Kansas City, Mo., USA) generated therandomization sequences, which were confidentially provided to thepackaging company. Treatment allocation was concealed by an identicalpackaging and labelling process performed by Aptuit, Inc. (Mount Laurel,N.J., USA). The study patients, obstetric care providers, studyinvestigators, study coordinators, and study monitors were blind to theexposure status (progesterone or placebo) of all study patients.

Once randomized, the subjects began treatment with the allocated studydrug and administered it daily until 37 weeks of gestational age,development of preterm rupture of membranes, or delivery. Subjects wererandomized in a 1:1 ratio to receive PROCHIEVE® 8% (vaginallyadministered 90 mg natural progesterone gel) or placebo vaginal gel. Allwomen performed self-dosing on a daily basis of their assigned studymedication, either PROCHEIVE® (progesterone) or placebo.

Example 1b Follow Up Regarding the Randomized, Double Blind, PlaceboControlled Test of the Effects of Progesterone on Preterm Birth

The data presented in this Example provides a further examination of thedata presented in Example 1a. The objective of this trial was todetermine whether prophylactic administration of vaginal progesteronereduces the risk of preterm birth in women with a history of spontaneouspreterm birth.

This trial was randomized, double-blind, placebo-controlled,multinational trial enrolled and randomized 659 pregnant women with ahistory of spontaneous preterm birth alone. Between 18 0/7 and 22 6/7weeks of gestation, patients were randomly assigned to once-dailytreatment with either 8% progesterone vaginal gel or placebo untildelivery, 37 weeks gestational age, or development of preterm rupture ofmembranes (PROM). The primary outcome was preterm birth at ≦32 weeks ofgestation. Statistical analysis was based on the intent-to-treatprinciple.

Pregnant women were eligible to enter the trial if they were between 18and 45 years of age with an estimated gestational age between 16 0/7 and22 6/7 weeks, and had a history of spontaneous singleton preterm birthbetween 20 0/7 and 35 0/7 weeks of gestation in the immediatelypreceding parity confirmed by review of medical records from thequalifying preterm birth. Patients were also required to understandEnglish or a common local language, provide a voluntarily signedinformed consent form, demonstrate an understanding of the purpose ofthe study, and agree to adhere to the study protocol.

Patients were excluded from the trial if they had a history of anadverse reaction to progesterone or any component present in thetreatment drug; had received treatment with progesterone within 4 weekspreceding enrollment; or were currently being treated for a seizuredisorder, psychiatric disorder, or chronic hypertension at enrollment.Patients were also excluded from the trial if they had a history ofacute or chronic congestive heart failure, renal failure, oruncontrolled diabetes mellitus; an active liver disorder; an HIVinfection with a CD4 count <350 cells/mm³ and requiring multipleantiviral agents; a placenta previa or low-lying placenta requiringvaginal precautions; a history or suspicion of breast or genital tractmalignancy; a history or suspicion of thromboembolic disease; or amüllerian anomaly. Patients who were currently or previously enrolled inanother investigational study within 1 month prior to screening for thepresent study were not included in the trial. Patients were alsorestricted from participation in the trial if the present pregnancy wascomplicated by a major fetal anomaly or a known chromosome disorder, orwas a multifetal gestation. Patients with a cervical cerclage in place,or those intending to have one placed during the current pregnancy, wereexcluded from study participation, as were those with signs of pretermrupture of membranes, vaginal bleeding, amnionitis, or preterm labor atenrollment. Finally, patients who were unable or unwilling to complywith the study procedures or had a qualifying preterm delivery thatoccurred without preterm labor were not included in the trial.

The study drug was packaged and labelled according to the 1:1randomization scheme provided by Quintiles, Inc (Kansas City, Mo., USA).A SAS (SAS Institute Inc., Cary, N.C., USA) procedure for variable blocksize was used to generate the randomization schedule stratified by studysite. Thirty-three of the 53 centers completed at least 1 randomizedblock accounting for 92% of the enrolled patients. The study drug(Prochieve® 8% progesterone gel) and placebo (Replens®) were provided byColumbia Laboratories, Inc. (Livingston, N.J., USA). Patients wereinstructed to self-administer the full applicator of vaginal gel atapproximately the same time daily, preferably in the morning. Patientsreceived a 2-week supply of the allocated treatment at the time ofrandomization, and at every 2-week study visit thereafter. All drugsupplies were to be brought in at each visit at all study centers, andcompliance with the study medication was determined from returned emptywrappers and unused wrappers. Percent compliance was assessed as totaltreatment duration compliance: (total applicators used/total dosingdays)×100. Total dosing days was defined as the interval from enrollmentto either the date of preterm premature rupture of membranes, the dateof preterm birth without accompanying ruptured membranes, or 37 0/7weeks' gestation.

The occurrence of adverse events was queried at each 2-week study visitat all centers by asking if the patient had any complaints or problems.Subjects received an extra 1-week drug supply when treatment wasinitiated in case they could not make the next regularly scheduledappointment. The study drug preparation is a bioadhesive formulation ofprogesterone for vaginal application consisting of a polycarbophil-basedgel that contains 8% (wt/wt) progesterone. A prefilled, single-use,disposable plastic applicator delivers the dose of 1.125 g of gelcontaining 90 mg of progesterone. The placebo was Replens®, thebioadhesive delivery system without the progesterone.

Subjects with a documented history of spontaneous preterm birth werescreened between 16 0/7 and 22 6/7 weeks of gestation by theinvestigator or study coordinator. The gestational age was based on thepatient's last menstrual period and correlated with an ultrasoundbiometry algorithm. Each patient had at least one ultrasound examinationbefore randomization to confirm gestational age and rule out major fetalanomalies, and a transvaginal scan to determine the length of thecervix. Subjects meeting the study criteria were enrolled by theinvestigator between 18 0/7 and 22 6/7 weeks to receive blinded studymedication. Following randomization, daily treatment was initiated bythe patient and continued until 37 0/7 weeks' gestational age,occurrence of preterm rupture of the membranes, or preterm delivery.Each patient was evaluated at 2-week intervals. At 28 weeks of gestationall subjects had another transvaginal ultrasound to determine cervicallength.

Baseline characteristics were similar in the two treatment groups.Progesterone did not decrease the frequency of preterm birth at ≦32weeks. There was no difference in the mean gestational age at delivery,infant morbidity or mortality, or other maternal or neonatal outcomemeasure. Treatment emergent adverse events were similar for the twogroups.

Based on these results, prophylactic treatment with vaginal progesteronegel does not effectively reduce the frequency of recurrent preterm birthin high-risk women selected by a history of spontaneous preterm birth.Other methods of risk assessment need to be studied.

A determination of the exact number of patients pre-screened at all 53study sites, including referral offices to these sites, was notconsidered feasible. An estimate of 1500 pre-screened subjects wasobtained by querying the study sites. A total of 711 women were definedas formally screened (informed consent obtained but not randomized), and42 were subsequently excluded. The most common reasons for exclusionafter consent were planned cerclage, comorbid conditions, and failure todocument previous spontaneous preterm birth at a qualifying gestationalage. A total of 669 patients were considered eligible for enrollmentinto the study, with 659 randomized to the two treatment groupsindicated for maternal history alone (FIG. 2). Nine patients enrolledinto the planned subinvestigation for short cervix alone and onequalifying patient lost to follow-up prior to randomization wereexcluded from the analysis. Patients who took at least one dose of studymedication and provided a delivery date were included in theintent-to-treat (ITT) population. Patients without a delivery date wereconsidered lost to follow-up.

The ITT population for previous preterm birth patients included 309patients in the progesterone group and 302 patients in the placebogroup. The randomization provided treatment groups that were wellmatched for age, ethnicity, and body mass index (BMI). Parity, number ofprior preterm births, and spontaneous abortions were also similar. Themean (±SD) gestational age at randomization was 19.9 (±2.1) and 20.1(±3.3) weeks for the progesterone and placebo groups, respectively. Withregard to prior pregnancy history, 76.4% of progesterone patients and74.5% of placebo patients had one previous spontaneous preterm birth,and 23.6% and 25.5% of subjects in each group had two or more previouspreterm births, respectively.

The rate of preterm birth at ≦32 0/7 weeks of gestation, the primaryoutcome, was not significantly different; 10.0% (n=31) in theprogesterone group and 11.3% (n=34) in the placebo group. In theanalysis of the primary outcome by country/region, no significantdifference existed between a country or region was observed. The meangestational age at delivery was 36.6 weeks for both the progesterone andplacebo groups. Compliance rates with the study medication were alsosimilar: 96.2% for women in the progesterone group and 96.4% for womenin the placebo group.

Other study outcomes also did not differ between the progesterone andthe placebo groups. The rate of preterm birth was 41.7% (n=129) versus40.7% (n=123), respectively, at <37 0/7 weeks; 22.7% (n=70) versus 26.5%(n=80), respectively, at ≦35 0/7 weeks; and 3.2% (n=10) versus 3.0%(n=9), respectively, at ≦28 0/7 weeks. The survival curves for time todelivery are shown in FIG. 5 a. Admissions for preterm labor (25.6% forprogesterone vs. 24.8% for placebo), administration of tocolyticmedications, and administration of antepartum corticosteroid therapywere similar between the two groups. In patients admitted for treatmentof preterm labor, the number of days from admission to delivery was 30for progesterone and 19.6 for placebo (95% CI, −23-2.3). In addition,there were no differences in the rate of preterm rupture of membranes(12.0% vs. 12.6%) or stillbirth/intrauterine fetal demise (1.6% vs.1.3%) in the progesterone and placebo groups, respectively.

The mean birth weight of the neonates in the progesterone and placebogroups was similar (2680±710 vs. 2661±738 gm, respectively), as was headcircumference (32.3±3.34 vs. 32.5±3.75 cm, respectively). There were nodifferences between treatment and placebo groups for the 1-minute(median score=8 for each) and 5-minute (median score=9 for each) APGARscores, or the rate of admission to a neonatal intensive care unit(17.5% vs. 21.5%). Occurrences of newborn respiratory distress syndrome(11.0% vs. 11.9%), grade 3 or 4 intraventricular haemorrhage (0.3% vs.0.3%), and necrotizing enterocolitis (1.0% vs. 1.7%) were also similarfor the progesterone and placebo groups. Congenital abnormalitiespotentially acquired in the second or third trimesters were observed in2 newborns: 1 case each of hip subluxation and pulmonic stenosis in eachgroup. Developmental abnormalities related to first-trimesterorganogenesis, such as hypospadias, extra digits, and tetralogy ofFallot, were not included. Infant follow-up data for 6, 12, and 24months of age are still being collected and not available at the time ofreporting of these results.

Example 2 Randomized Trial Investigating the Efficacy of VaginalProgesterone to Prevent Early Preterm Birth in Women with a ShortenedCervix in the Midtrimester

The study further included women without a history of preterm birth andhaving a short cervix at the time of enrollment. Although the shortcervix only population included 9 patients, the results suggested apossible effect of progesterone with 40% (2/5) delivering ≦32 weeksgestation on placebo and 0 (0/4) delivering ≦32 weeks gestation onprogesterone. As some participants with a history of prior preterm birthalso had a short cervix, the preterm birth study population was dividedinto quartiles based on cervical length. The lowest quartile (≦3.2 cm)was combined with the short cervix only patients and subdividedsequentially and the primary and secondary outcomes for women withcervical lengths of ≦3.0 cm and <2.8 cm at the time of enrollment wereanalyzed. There were an insufficient number of patients with evenshorter cervical lengths available for further analysis. For thepurposes of the study, the criteria for short cervix was set at lessthan 2.8 cm. A total of 46 participants fell into this category, andtheir demographics and characteristics are set forth in FIG. 3.

Generally, a cervical length <2.8 cm was identified in 46 randomizedwomen: 19 of 313 who received progesterone and 27 of 307 who receivedplacebo. Baseline characteristics of the two groups were similar. Therate of preterm birth at ≦32 weeks was significantly lower forprogesterone than placebo (0% vs. 29.6%, P=0.014). With progesterone,there were fewer NICU admissions (15.8% vs. 51.9%, P=0.016) and shorterNICU stays (1.1 vs. 16.5 days, P=0.013). There was also a trend toward adecreased rate of neonatal respiratory distress syndrome (5.3% vs.29.6%, P=0.060). It was determined that vaginal progesterone gel reducesthe rate of early preterm birth and improves neonatal outcome in womenwith mid-trimester cervical shortening.

The study included women with a documented history of spontaneouspreterm birth (<35 weeks) in a singleton pregnancy in the immediatepreceding parity regardless of cervical length, and women without ahistory of preterm birth but with midtrimester cervical shortening (≦2.5cm) in the current pregnancy were offered enrollment in the study at 180/7-22 6/7 weeks of gestation. Recruitment began in April 2004 and thelast patient delivered Jan. 8, 2007.

Women were excluded from the study if they had a condition orcomplication of pregnancy prior to screening that increased the maternalor fetal risk of an adverse outcome, significantly increased the risk ofa medically indicated (nonspontaneous) preterm birth, or would likelyresult in lack of compliance or early discontinuation of the study.Therefore, women were excluded if any of the following conditions werepresent: age <18 or >45 years; multifetal gestation; history of anadverse reaction to progesterone or any component present in thetreatment medication; treatment with progesterone within 4 weekspreceding enrollment; or current treatment for a seizure disorder,psychiatric disorder, or chronic hypertension. Patients were alsoexcluded from the trial if they had a history of acute or chroniccongestive heart failure, renal failure, or uncontrolled diabetesmellitus; an active liver disorder; an HIV infection with a CD4 count<350 cells/mm³ and requiring multiple antiviral agents; a placentaprevia or low-lying placenta and placed on vaginal precautions; ahistory of breast or genital tract malignancy; a thromboembolism; or amüllerian anomaly. Patients who were currently or previously enrolled inanother investigational study within one month prior to randomizationwere not included.

Patients were also restricted from participation in the trial if thepresent pregnancy was complicated by a major fetal anomaly or a knownchromosome disorder. Patients with a cervical cerclage in place, orthose intending to have one placed during the current pregnancy, wereexcluded from the study, as were those with signs of preterm rupture ofmembranes, vaginal bleeding, amnionitis, or preterm labor at enrollment.

Women with a history of spontaneous preterm birth in the precedingpregnancy regardless of cervical length or women without a history ofpreterm birth but with midtrimester cervical shortening in the currentpregnancy were screened by the investigator or study coordinator between16 0/7 and 22 6/7 weeks of gestation. Prior history of spontaneouspreterm birth was confirmed by evaluation of the patient's medicalrecords before enrollment. Gestational age was based on the patient'slast menstrual period and correlated with an ultrasound biometryalgorithm. Each patient had at least one ultrasound examination beforerandomization to confirm gestational age and rule out major fetalanomalies, and a transvaginal scan to determine the length of thecervix. Subjects meeting the study criteria were enrolled by theinvestigator between 18 0/7 and 22 6/7 weeks and received identicallypackaged, sequentially numbered progesterone or placebo vaginal gel in a1:1 ratio. A SAS (SAS Institute Inc., Cary, N.C., USA) procedure forvariable block size was used to generate a randomization schedulestratified by study site and by inclusion criteria (prior preterm birthor short cervix). Quintiles, Inc. (Kansas City, Mo., USA) generated therandomization sequences, which were confidentially provided to thepackaging company. Treatment allocation was concealed by an identicalpackaging and labelling process performed by Aptuit, Inc. (Mount Laurel,N.J., USA). The study patients, obstetric care providers, studyinvestigators, study coordinators, and study monitors were blind to theexposure status (progesterone or placebo) of all study patients.

Following randomization, daily treatment was initiated by the patientand continued until 37 0/7 weeks' gestational age, occurrence of pretermrupture of membranes, or delivery. Each patient was evaluated at 2-weekintervals. All subjects had another transvaginal ultrasound to determinecervical length at 28 weeks of gestation.

Prior to beginning the study, baseline measurements of each of theparticipant's cervical length were taken and are summarized in FIG. 1.During the study, cervical length measurements were made by ultrasoundat both baseline and later at 28 weeks after a period of 6-10 weeks ofdosing. The mean cervix length of 3.7 cm was the same for both thetreatment and placebo groups, and the range of cervical length for allparticipants was between 1.1 cm and 7.9 cm. At 28 weeks gestation, eachparticipant's cervix was re-measured and the data was compared to thebaseline data, and an unexpected and surprising finding was discovered.As shown in FIG. 4, the mean decrease in cervix length after 28 weeksfor participants in the placebo group was 0.61 cm, while the meandecrease in cervix length over the same period of time for thoseparticipants in the treatment group (i.e., on the progesterone regimen)was only 0.44 cm. Because the p-value for the overall test was 0.038,the results indicate that there was a statistically significant decreasein the amount of shortening or effacing of the cervix length for womenon the progesterone regimen compared to women taking placebo.

The results of the study are depicted using Kaplan-Meier curves as shownin FIGS. 5 b-10, examining the preterm birth endpoint in the study. FIG.5 b is a curve for time to delivery for all randomized patients. Thoughthe curves for each group in FIG. 5 b appear to have substantialoverlap, when the results are broken down further for analysis bypatient cervical length at baseline, the difference in outcome betweenthe treatment and placebo groups is clearly visible. For patients havinga baseline cervical length of less than or equal to 3.2 cm, (FIG. 6),less than or equal to 3.0 cm (FIGS. 8 and 9), and less than 2.8 cm (FIG.10), participants in the treatment group clearly exhibited a probabilityof not delivering over a longer gestation period compared toparticipants in the placebo group. As shown in FIG. 7, no statisticallysignificant difference in outcome was reflected between the treatmentand placebo groups in patients having a baseline cervical length greaterthan 3.2 cm at baseline.

Referring to FIG. 10, which shows the probability of patients withbaseline cervical length less than 2.8 cm remaining undelivered, theparticipant group having a cervical length of less than 2.8 cmexperienced a significant reduction in the frequency of preterm birth.As shown in FIG. 10, among 46 subjects (19 treated with progesterone,e.g., Prochieve® brand progesterone, and 27 placebo) the frequency ofpreterm birth in the treatment group was 0%, vs. 29.6% in the placebogroup (P=0.014). For the purposes of this study, parameter for pretermbirth was set at less than or equal to 32 weeks. FIG. 11 includes a moredetailed breakdown of delivery at various points of gestation for theprogesterone and the placebo groups, namely for less than or equal to37, 35, 32, and 28 weeks. The outcome was markedly improved for thetreatment group over the placebo group at each time point. Specifically,for less than or equal to 37 and less than 35 weeks, treatment reducedthe number of preterm delivery by about half, and for less than or equalto 32 and less than or equal to 28 weeks, there were no pretermdeliveries in the treatment group, though there were 8 and 3 pretermdeliveries, respectively, in the placebo group.

Study results also revealed an improved outcome for neonates born toparticipants in the progesterone group, which is shown in FIG. 12. Whenadministered to women with a cervical length <2.8 cm, progesteronetherapy reduced the number of admissions to the NICU (15.8% vs. 51.9%,P=0.016) and decreased the length of NICU stay (1.1 vs. 16.5 days,P=0.013). There was a trend toward a reduction in total neonatalhospital days (5.8 vs. 18.2 days, P=0.055) and decreased occurrence ofneonatal respiratory distress syndrome (5.3% vs. 29.6%, P=0.060) withprogesterone therapy.

In the subgroup of women enrolled with a cervical length of <2.8 cm, 2fetal/infant deaths occurred in the placebo group ([1] term, expired at11 months of age, SIDS; [2] 35 weeks of gestation, aspiration pneumonia)and none in the vaginal progesterone group.

Based on the results of this study, it is evident that administeringprogesterone to pregnant women effectively decreases the amount ofshortening or effacing of their cervixes, most notably in women withshort cervixes.

Example 3 Population Having a Baseline Cervical Length of <2.8 cm

The data for a subgroup of participants having a baseline cervicallength of less than or equal to 2.8 cm is provided in Table 1 below. Theresults show that 8 of the 27 participants who received the placeboregimen gave birth earlier than 32 weeks, while none of the 19participants who received the progesterone regimen gave birth earlierthan 32 weeks. As indicated by the two-sided p-value of 0.014 and the95% CI −0.469, −0.124, the results indicate the statisticallysignificant effect in the reduction of births before 32 weeks byadministration of progesterone compared to placebo among a population ofpregnant women having a baseline cervical length of ≦2.8 cm. See alsoFIGS. 12 and 14 a-e, which provide a comparison between treatments forinfant outcomes of patients using placebo versus patients usingProchieve® progesterone.

TABLE 1 Births >32 Births ≦32 Weeks Weeks Total Placebo Group Number 198 27 Treatment Group Number 19 0 19 Total 38 8 46 Fisher's 0.014 ExactTest p-Value 95% CI −0.469, −0.124

Example 4 Population Having a Baseline Cervical Length of ≦3.0 cm

The data for a subgroup of participants having a baseline cervicallength of less than or equal to 3.0 cm is provided in Table 2 below. Theresults show that 11 of the 58 participants who received the placeboregimen gave birth at 32 weeks or earlier, while only 5 of the 58participants who received the progesterone regimen gave birth at 32weeks or earlier. These results are significant according to the 95% CIand the 2-sided p-value indicates a trend for the effect in thereduction of births before 32 weeks by administration of progesteronecompared to placebo among the population of pregnant women having abaseline cervical length of ≦3.0 cm. See also FIGS. 13 a-e, whichprovide a comparison between treatments for infant outcomes of patientsusing placebo versus patients using Prochieve® progesterone.

TABLE 2 Births >32 Births ≦32 Weeks Weeks Total Placebo Group Number 4711 58 Treatment Group Number 54 4 58 Total 101 15 116 Two-sided 0.094 Pr≦ P 95% CI −0.214, −0.001

The term “about,” as used herein, should generally be understood torefer to both the corresponding number and a range of numbers. Moreover,all numerical ranges herein should be understood to include each wholeinteger within the range.

While illustrative embodiments of the invention are disclosed herein, itwill be appreciated that numerous modifications and other embodimentscan be devised by those of ordinary skill in the art. Features of theembodiments described herein can be combined, separated, interchanged,and/or rearranged to generate other embodiments. Therefore, it will beunderstood that the appended claims are intended to cover all suchmodifications and embodiments that come within the spirit and scope ofthe present invention.

1. A method for treating or preventing the onset of preterm labor andsubsequent preterm birth in a pregnant woman with a short cervixcomprising: determining to treat or prevent short cervix in a pregnantwoman in order to maintain or prolong gestation; and administering aneffective amount of a formulation containing progesterone sufficient toprolong gestation by minimizing the shortening or effacing of thecervix.
 2. The method of claim 1, wherein the method further comprisesmonitoring or confirming the reduction in cervical shortening oreffacement after the administration of said progesterone.
 3. The methodof claim 1, wherein the formulation is administered vaginally and is: a)in the form of a gel, cream, suppository, or solid dosage form; or b) isreleased by a suitable delivery device.
 4. The method of claim 1,wherein the progesterone comprises one or more of the following: anatural progesterone, a metabolite or progesterone, or a syntheticprogesterone.
 5. The claim 4, wherein the progesterone is naturalprogesterone.
 6. The claim 5, wherein said natural progesterone isadministered vaginally.
 7. The method of claim 4, wherein theprogesterone comprises on or more synthetic progesterones.
 8. The methodof claim 7, wherein said synthetic progesterone is administeredvaginally.
 9. The method of claim 7, wherein said synthetic progesteroneis selected from a group consisting of one or more of the following:medroxyprogesterone acetate, norethindrone, norethindrone acetate,norethindrone enanthate, desogestrel, leveonorgestrel, lynestrenol,ethynodiol diacetate, norgestrel, norgestimate, norethynodrel,gestodene, drospirenone, trimegestone, levodesogestrel, gestodyne,nesterone, etonogestrel, and derivatives from 19-nor-testosterone. 10.The method of claim 1, wherein said progesterone is administered dailybeginning about the 18^(th) to 22^(nd) week of gestation until about the37^(th) week of gestation.
 11. The method of claim 1, wherein the amountof progesterone that is administered is between about 45 mg and 800 mg.12. The method of claim 1, wherein the progesterone is administered viaa drug delivery system that comprises progesterone, a water-soluble,water-swellable cross-linked polycarboxylic acid polymer, and at leastone adjuvant.
 13. The method of claim 1, wherein the progesterone isadministered to a pregnant woman whose cervix has a length between 1.0cm and 8.0 cm.
 14. The method of claim 1, wherein the progesterone isadministered to a pregnant woman whose cervix has a length between 1.0cm and 3.0 cm.
 15. The method of claim 1, wherein the progesterone isadministered to a pregnant woman whose cervix has a length between 1.0cm and 2.5 cm.
 16. The method of claim 1, wherein the progesteronecomprises both natural progesterone and 17-alpha-hyroxyprogesteronecaproate.
 17. The method of claim 16, wherein the progesterone isadministered for about 21 weeks.
 18. The method of claim 16, wherein theprogesterone is administered beginning about the 2^(nd) to 4^(th) weekof gestation.
 19. The method of claim 11, wherein the progesterone isadministered as early as gestation.
 20. The method of claim 11, whereinthe amount of progesterone that is administered is about 90 mg and theprogesterone is natural progesterone administered vaginally.